Neil2-null mice accumulate oxidized DNA bases in the transcriptionally active sequences of the genome and are susceptible to innate inflammation

Anirban Chakraborty, Maki Wakamiya, Tatiana Venkova-Canova, Raj K. Pandita, Leopoldo Aguilera-Aguirre, Altaf H. Sarker, Dharmendra Kumar Singh, Koa Hosoki, Thomas Wood, Gulshan Sharma, Victor Cardenas, Partha Sarkar, Sanjiv Sur, Tej K. Pandita, Istvan Boldogh, Tapas Hazra

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Why mammalian cells possess multiple DNA glycosylases (DGs) with overlapping substrate ranges for repairing oxidatively damaged bases via the base excision repair (BER) pathway is a long-standing question. To determine the biological role of these DGs, null animal models have been generated. Here, we report the generation and characterization of mice lacking Neil2 (Nei-like 2). As in mice deficient in each of the other four oxidized base-specific DGs (OGG1, NTH1, NEIL1, and NEIL3), Neil2-null mice show no overt phenotype. However, middleaged to old Neil2-null mice show the accumulation of oxidative genomic damage, mostly in the transcribed regions. Immunopulldown analysis from wild-type (WT) mouse tissue showed the association of NEIL2 with RNA polymerase II, along with Cockayne syndrome group B protein, TFIIH, and other BER proteins. Chromatin immunoprecipitation analysis from mouse tissue showed co-occupancy of NEIL2 and RNA polymerase II only on the transcribed genes, consistent with our earlier in vitro findings on NEIL2's role in transcription-coupled BER. This study provides the first in vivo evidence of genomic region-specific repair in mammals. Furthermore, telomere loss and genomic instability were observed at a higher frequency in embryonic fibroblasts from Neil2-null mice than from the WT. Moreover, Neil2-null mice are much more responsive to inflammatory agents than WT mice. Taken together, our results underscore the importance of NEIL2 in protecting mammals from the development of various pathologies that are linked to genomic instability and/or inflammation. NEIL2 is thus likely to play an important role in long term genomic maintenance, particularly in long-lived mammals such as humans.

Original languageEnglish (US)
Pages (from-to)24636-24648
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number41
DOIs
StatePublished - Oct 9 2015

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Neil2-null mice accumulate oxidized DNA bases in the transcriptionally active sequences of the genome and are susceptible to innate inflammation'. Together they form a unique fingerprint.

  • Cite this

    Chakraborty, A., Wakamiya, M., Venkova-Canova, T., Pandita, R. K., Aguilera-Aguirre, L., Sarker, A. H., Singh, D. K., Hosoki, K., Wood, T., Sharma, G., Cardenas, V., Sarkar, P., Sur, S., Pandita, T. K., Boldogh, I., & Hazra, T. (2015). Neil2-null mice accumulate oxidized DNA bases in the transcriptionally active sequences of the genome and are susceptible to innate inflammation. Journal of Biological Chemistry, 290(41), 24636-24648. https://doi.org/10.1074/jbc.M115.658146